Journal of Neuroscience Methods 75 (1997) 147 – 154

AVERAGE: a Windows® program for automated analysis of event

related cerebral blood flow

M. Deppe *, S. Knecht, H. Henningsen, E.B. Ringelstein

Department of Neurology, Uni6ersity of Münster, Albert -Schweitzer -Str. 33, 48129 Münster, Germany

Received 5 December 1996; accepted 15 March 1997

Abstract

Functional transcranial Doppler sonography (fTCD) is used to measure changes in brain perfusion during different states of
brain activity by evaluating flow velocities within the major brain arteries. We developed a computer program called AVERAGE
which can be used with various TCD devices and allows for subtle quantitative off-line analysis of Doppler flow signals.
AVERAGE supports data transformation, heart beat analysis, noise reduction, trigger signal and marker modification, artifact
analysis and artifact rejection, as well as data reduction. Perfusion differences and their time course within two different arteries
can be analyzed by parametric and non parametric statistical methods. This is important, for instance, in studies on hemispherical
dominance during mental task processing. Each data processing step is supported by graphical output. If investigated bilaterally
with interhemispheric analysis even minimal activations can reliably be detected and quantified with a sensitivity known from
positron emission tomography approaches. © 1997 Elsevier Science B.V.

Keywords: Data analysis; Functional transcranial Doppler ultrasonics; Computer software; Evoked flow; Averaging

1. Introduction techniques in the presurgical assessment of hemispheric

Functional transcranial Doppler ultrasonography
(fTCD) allows to assess brain activation by measuring
cerebral blood flow velocity (CBFV) changes in the
basal arteries. It provides temporal information on
cerebral activation complementary to that obtained by
perfusion positron emission tomography (PET) or func-
tional magnetic resonance imaging (fMRI) (Sitzer et al.,
1994).
TCD has been applied to evaluate flow velocity
changes associated with cognition, vision, language or
attention (e.g. Aaslid, 1987; Conrad and Klingelhöfer,
1989; Droste et al., 1989a,b; Kelley et al., 1992; Markus
and Boland, 1992; Bäcker et al., 1994; Hartje et al.,
1994; Silvestrini et al., 1994; Rihs et al., 1995). There is
hope that fTCD may even be able to replace invasive
* Corresponding author. Tel.: +49 251 8348174; fax: +49 251
8348181; e-mail: Deppe@uni-muenster.de
language dominance (Knecht et al., 1996).
While TCD’s spatial resolution is confined to major
artery territories, as opposed to the good spatial resolu-
tion of PET and most fMRI approaches, it has an
excellent temporal resolution and provides continuous
information of cerebral perfusion changes associated
with functional cortical activation. Given the growing
importance of TCD as a diagnostic and scientific tool
there is need for an easily applicable, inexpensive, sensi-
tive and reliable technique for CBF analysis on a
routine basis.
Mostly, the analysis of event related CBFV changes
is based on the time-locked averaging of TCD signals
linked to specific stimuli, and is similar to the analysis
of electroenzephalographic evoked potentials (EPs). In
TCD studies, the characteristic time scale of the perti-
nent signal intervals (typical duration 30–60 s) is about
100 times larger than in EP studies. Therefore, with
TCD the number of epochs which can be acquired

0165-0270/97/$17.00 © 1997 Elsevier Science B.V. All rights reserved.

PII S 0 1 6 5 - 0 2 7 0 ( 9 7 ) 0 0 0 6 7 - 8
148 M. Deppe et al. / Journal of Neuroscience Methods 75 (1997) 147–154

Fig. 1. Example setup of a fTCD study for the assessment of attention and language dominance (Knecht et al., 1996). Two ultrasound probes are
mounted on both temples of a volunteer and are adjusted for assessment of the blood flow velocity of the left and right middle cerebral arteries
(MCAs). The cerebral blood flow velocity (CBFV), displayed in the middle column as typical raw signal with signal modulations due to heart beat,
is recorded simultaneously with trigger signals by a TCD device. One trigger channel represents the occurrence of a letter on the computer screen
and the other a preceding cueing tone. The simultaneous recording guarantees the synchronization between stimulation and CBFV response.
Details of the study are described in Knecht et al., 1996. Data analysis is performed off-line by the analysis software AVERAGE 1.30 described
in the present work.

without fatiguing subjects is reduced to a maximum of
20 –40, corresponding to a recording time of about
20 –40 min. This considerably limits the possibility of
noise reduction by plain averaging. Evoked CBFV
modulations are superimposed by more then ten times
larger spontaneous blood flow velocity oscillations due
to heart beat, respiration and slow, spontaneous peri-
odical fluctuations (e.g. the TCD equivalents of B-
waves; Diehl et al., 1991; see also Droste et al., 1993;
1994; Zunker et al., 1996). This wide range of physio-
logical modulations and additional artificial changes of
the CBFV signal, see below, must be accounted for. A
detailed description of how this can be accomplished is
provided in this article.
Recent studies (Bäcker et al., 1994; Schimke et al.,
1994; Deppe et al., 1995; Diehl et al., 1996; Knecht et
al., 1996), employing the computer program described
below, demonstrated that appropriate management of
spontaneous CBFV oscillations, as well as artifacts,
significantly improve the sensitivity of fTCD and allows
its use as a clinical tool. An experimental setup of a
fTCD study used in our group for the assessment of
attention and language dominance is shown in Fig. 1.
2. Implementation
The software AVERAGE (Version 1.30) was devel-
oped by one of the authors (M. D.) in the object-ori-
ented programming language Borland® C++ 3.1
(Borland International) and consists of about 14 000
lines of source code. The minimal requirements are an
IBM®-compatible PC driven by an Intel® 80386 CPU
or higher with Microsoft Windows® 3.1 and 8 Mbytes
memory. AVERAGE has also been tested for Win-
dows® NT Version 3.5, 3.51, 4.0 (16 Mbytes memory)
and Windows® 95. The data capability only depends on
the amount of available memory. Configured with 8
Mbytes memory, AVERAGE can, for example, process
10 simultaneously measured channels with a total
amount of 100 000 sampled data points per channel.
The latter represents, for example, a recording time of
about 2 h with a sample rate of 14 Hz.
In the following sections the functional aspects of
AVERAGE will be described according to its menu
items.
3. Data import
The raw data of a TCD flow signal, i.e. mostly the
maximal blood flow velocity represented by the so-
called envelope curve of the TCD spectrum, can di-
rectly be read if they are acquired with the following
TCD machines: Multiflow, Multidop P, Multidop T,
Multidop X, Multidop X2 and Multidop X4 (DWL®,
Sipplingen, Germany) running under the software
MDT7® or TCD7® (DWL®). These systems are also
capable of recording simultaneously to the TCD signals
analog data channels as well as time marker informa-
tion. Additionally, AVERAGE supports an import op-
tion for ASCII text files, containing multiple
simultaneously acquired raw data channels, so that
data recorded by other TCD devices can be evaluated
as well.
 M. Deppe et al. / Journal of Neuroscience Methods 75 (1997) 147–154
4. Trigger signal modification
Most stimulation devices provide reliable analog or
digital trigger output which represents the stimulation
event as a short voltage pulse. If however, a reactio
or response by the subject represented by an elec-
tronic signal (e.g. the electromyogram) serves as a
trigger event, the signal characteristics indicating this
event have to be defined. The goal of AVERAGE’s
marker transformation step is to transform sampled
signal pulses into a uniform digital sequence of ‘0’ or
‘1’ which can be unequivocally interpreted by the av-
eraging algorithm. Digit ‘1’ indicates that a marker
has been set at the respective time point. During the
transformation, the algorithm sets all data points
which are lower than a threshold Tl to ‘0’. The first
sampled point which is larger than Tl and less than
an upper threshold Tu will be stored as ‘1’ in the
marker channel. The following N sampled points will
be set to ‘0’, irrespective of their value. N is an in-
teger value which can be selected by the user and
must be larger than the expected maximum trigger
pulse duration (unit: s) times the sample rate (unit:
Hz). The procedure will be repeated until all data
points are modified. It is possible to choose any non
zero rational number instead of ‘1’ as marker value.
This particular option permits to have two or more
classes of markers indicating different events on the
same marker channel. Markers can be deleted off-
line, moved (i.e. latency corrected) or can be added
manually for those setups which do not allow for
automated event-correlated recording of trigger sig-
nals (for example Diehl et al., 1996). Preprocessing of
the trigger channel by supported mathematical opera-
tions for integration, differentiation or band pass
filtering in combination with the marker transforma-
tion step has the advantage of employing a wide
range of trigger sources.
5. Data transformation
5.1. Normalization
At the input stage, the software supplies descriptive
statistics (mean, median, range, standard deviation)
for the raw data. Based on this information the raw
data can be transformed to relative units (e.g. mean
100%) by standard mathematical operations which are
supported by menu options. Thus, one could also
correct CBFV data for end-tidal CO2 pressure (Mark-
walder et al., 1984). In contrast to relative units, the
blood flow velocity 6 and its evoked modulations
show large interindividual variations if described in
absolute physical units (Ringelstein et al., 1990). Fur-
thermore, absolute values have the disadvantage of
being sensitive to the insonation angle a between the
149
ultrasound beam and the course of the insonated
artery. (Aaslid, 1992):
c Df
6= (1)
2f0 cos(a)
(c, ultrasound velocity in tissue; f0, transmission fre-
quency of ultrasound transducer; Df, Doppler fre-
quency shift)
The difference
D6=61 ⌧ 62 (2)
of the simultaneously measured velocities 61 and 62 of
two arteries inherently depends on the insonation an-
gles a1 and a2, and the same problem arises if perfusion
asymmetries are described as velocity quotients
6Q =61/62 (3)
A crude estimation of the flow changes due to cerebral
activation can be provided by the Eq. (2) or Eq. (3)
with an accuracy sufficient for qualitative purposes (e.g.
O’Dell et al., 1992; Kelley et al., 1992; Njemanze and
Gomez, 1992; Silvestrini et al., 1994; Rihs et al., 1995).
However, if perfusion differences between hemispheres
are small or must be quantified, in language lateraliza-
tion indices, a systematic error can be caused by differ-
ent velocity weighting factors such as the insonation
angle (i.e. cos(a)). For example, if the left ultrasound
probe is mounted at an insonation angle of a1 =45°
and the right one at a2 = 50°, blood flow velocity
changes of both arteries are weighted differently by
10% (cos(45°)/cos(50°) = 1.10). To normalize blood
flow velocities by the mean flow velocity measured
during the whole examination time (Sitzer et al., 1992)
has the drawback that this mean value will be modified
by the evoked blood flow velocity responses and the
magnitude of relative evoked responses would depend
on the duration of the activation.
AVERAGE supplies optional automatic data nor-
malization separately for each stimulation trial accord-
ing to the equation:
6 rel = 6/6 mean, (4)
where 6mean is the mean blood flow velocity assessed
during freely selectable time periods assumed not to be
influenced by the stimulation (‘resting phases’). In our
experiments, we chose the 15-s period before stimula-
tion (pre-trigger-interval). Perfusion differences between
two arteries are then given as:
D6 rel = 6 rel
1 ⌧6 2
rel
c Df1 2f0 cos(a1) c Df2 2f0 cos(a2)
= ⌧
2f0 cos(a1) c Df mean
1 2 f 0 cos(a2) c Df 2
mean
Df 1 Df2
= ⌧ mean (5)
Df 1
mean
Df 2
and are independent of the probe’s angles.
150 M. Deppe et al. / Journal of Neuroscience Methods 75 (1997) 147–154

Fig. 2. (A) Comparison of an envelope curve of a typical TCD spectrum of the blood flow velocity in the middle cerebral artery and the
corresponding heart cycle integrated function. The mean velocity is not affected by the integration. The step width represents the systole-to-systole
interval. Velocities are transformed to relative values (mean 100%). (B) Velocity frequency distribution of the envelope curve. The abscissa
represents recorded CBFV values with a rate of 14 samples per second over an acquisition period of 20 min. The bimodal histogram shows
relevant and highly significant (p B 0.001, Kolmogorov-Smirnov test) differences between the expected normal distribution (continuous curve)
based on mean velocity and standard deviation. (C) The velocity frequency distribution after heart cycle integration. Normal distribution was not
rejected. The mean (100%) is represented by the most frequent velocity value.

5.2. Heart cycle detection
Fig. 2A shows a typical raw data signal with ampli-
tude fluctuations of up to 80% due to heart beat. The
beginning of a cardiac cycle is defined as the point of
inflexion of the systolic flow increase. These points are
determined by a peak analysis in the time domain of
the first derivative of the CBFV raw data and can be
stored into an additional channel as heart beat marker
(HBM).
5.3. Artifact detection
More than one HBM per pulsatility interval (systole-
to-systole interval and phase estimated by Fourier-
Analysis of a 10 s time interval) or markers differing by
more than 300 ms from the most likely latency in
occurrence of the corresponding expected systole are
classified as artifacts. The latencies of these artificial
HBM can be stored automatically as artifact markers in
an existing or new data channel (artifact channel). They
indicate signal disturbances which can be caused by
probe displacement, coughing, speaking or external in-
terruptions of the examination session. Fig. 3 (left
panel) illustrates, how the graphical user interface dis-
plays an artifact marker, correlated to disturbances of
the blood flow velocity curve.
5.4. Frequency domain filtering
Low pass signal filtering was introduced into fTCD
studies in order to reduce the disturbing blood flow
velocity modulations due to vessel wall motion (Aaslid,
1987). This filtering is supported by AVERAGE as a
menu option. (For details of the implementation used
see Press et al., 1992) However, low pass filtering
constitutes a tradeoff between an effective noise reduc-
tion and a good time resolution. Filtering of cerebral
blood flow velocity curves with a low cut-off frequency
of less than 0.4 Hz can cause shifts in the latency of
sharp velocity peaks. Additionally, artificial signal over-
shoot and undershoot may occur (Regan, 1989, Sec-
tions 1.2.9 and 1.2.11).
5.5. Heart cycle integration
A new, very effective method to reduce modulations
of BFV due to rhythmic myocardial contractions is
heart cycle integration (HCI) of TCD velocity curves.
The HCI algorithm replaces the raw data envelope
curve by a step function where the width of steps
corresponds to the cardiac intervals and the height
represents the mean blood flow velocity within these
intervals (Fig. 2A, step curve). Therefore HCI does not
influence mean flow velocity. In contrast to low-pass
filtering in the frequency domain, HCI does neither
introduce any artificial correlation of the mean flow
velocities of two successive cardiac cycles, nor any
phase errors like those produced by ‘moving average’
methods. The latter are frequently supported by com-
mercially available data analyzing tools for smoothing
of time series (DSP Development Corporation, 1991a).
Heart cycle-integrated data offers a further interest-
ing feature. If the mean flow velocities in two different
 M. Deppe et al. / Journal of Neuroscience Methods 75 (1997) 147–154 151

Fig. 3. Example screen shot of AVERAGE’s graphical user interface. The results of each data processing step can be displayed by separate data
windows. As an example of the artifact managing capabilities a disturbed raw data signal is shown before (upper left window) and after heart cycle
integration (upper right window). The signal disturbance is detected and noted as an artifact marker in the artifact channel (lower left panel). The
user has the option to reject completely the data of the corresponding stimulation trial from further analysis or to replace the data within the
affected cardiac interval by the mean, calculated from the two neighboring cardiac cycles. The lower right window displays in percentages the
averaged time course of blood flow velocity changes of the left (black line) and right (gray line) middle cerebral artery during 15 successive trials
of mental word generation. The abscissa represents the time interval of the so called ‘epoch’ and is scaled in seconds. Word generation began 5
s after a cueing tone, which occurred at latency t = 0 s (Knecht et al., 1996). The last representation is useful for determining the optimal
inter-stimulus interval, because it provides information about the ‘relaxation time’ of the activation, i.e. the time point when the evoked blood flow
increase is decayed to the baseline.

arteries supplying different regions of the brain are 6. Averaging

compared by statistical methods in order to assess the
significance and confidence limits of flow changes, it is
necessary to estimate the probability distribution of the
velocities acquired from different vessels. In the case of
the raw TCD signal shown in Fig. 2A, the velocity
histogram approximates a bimodal distribution (Fig.
2B). A similar characteristic occurred even when the
data were filtered by a usual low-pass of 0.5 Hz. In case
of a bimodal velocity probability distribution, neither
mean nor median value are useful to characterize the
central velocity, because they will provide only a ‘com-
promise’ value between the two peaks. Statistical con-
siderations (see below) would be unnecessarily complex,
because a parametrical description of the data by a
gaussian bell curve for expected normal distribution is
not appropriate. In contrast to this, the frequency
distribution of the heart cycle integrated data can be
estimated by a normal distribution (Fig. 2C). In this
case conventional statistics like a Student’s t -test or an
analysis of variance (ANOVA) can be applied to com-
pare mean velocities between arteries (Spence et al.,
1990).
The sub-menu a6erage provides an item called ‘start’
to average time-locked to the stimulation event the
simultaneously acquired signals and offers the option to
modify the following parameters:
6.1. Epoch definition
The user can choose the time interval (epoch) relative
to the stimulus by a dialog box. Both, the pre-trigger
interval, i.e. the period preceding the trigger, indicated
by negative latencies, and the subsequent ‘post-trigger
interval’ can be defined (compare Fig. 3, lower right
panel).
6.2. Marker range
Stimuli of different sorts can be identified by differ-
ent numerical values for their corresponding marker
(see Section 4). Epochs related to one stimulation
paradigm can be selected for averaging by appropriate
choice of the upper and lower threshold of the marker
value.
152 M. Deppe et al. / Journal of Neuroscience Methods 75 (1997) 147–154
6.3. Artifact filtering
The minimum and maximum and the range of the
signal amplitude within each epoch is calculated for all
data channels. If one of these parameters exceeds a
freely definable threshold the epoch is rejected from
averaging by a filter. In addition to the filtering of
nonphysiological data (e.g. CBFV values less than 30%
and more than 200% of the raw data mean) this mech-
anism permits to also reject epochs of which a marker
has been set at a value above a certain threshold. These
markers are put on the so called artifact channel. This
channel can contain markers which are set on-line (e.g.
by a switch), off-line or which are determined by the
above artifact detection.
6.4. Baseline correction
To remove the influence of slow spontaneous fluctua-
tions or shifts, e.g. the mean flow velocity and the heart
rate often decrease slightly during the examination, a
baseline correction is also provided. Any arbitrary
range within an epoch can be defined as baseline inter-
val. The mean of this range will be subtracted from the
corresponding epoch. The software suggests the pre-
trigger interval as default range for baseline correction.
During experiments however, where the subjects are
anticipating the stimulus, the range can be shifted to
earlier, more appropriate latencies (e.g. 5– 20 s before
the trigger).
6.5. Start
The average process can be started by this menu item
after the desired trigger channel has been selected and
the average mode has been set. The average mode has
two options: mean and median.
6.6. Parametrical description of results
In the ‘mean mode’ the arithmetical mean epoch of
all non rejected epochs and the corresponding standard
deviation are calculated for each channel including the
trigger channel. Overlapping epochs can easily be de-
tected since within this case the averaged trigger chan-
nel shows more than one peak. The mean epoch and
the standard error can be displayed and instantly saved
as graphs. AVERAGE offers the option to save all
transformed and accepted epochs as ASCII-files or as
DADISP® compatible datasets for further analysis or
for graphical display with commercial software.
6.7. Nonparametrical description of results
If the ‘median mode’ is used, mean and standard
deviation are substituted by median, lower and upper
quartile. These estimators for the data’s central value
and their spread are robust against ‘outliers’, which can
markedly influence the mean, particularly with a low
number (e.g. 20–40) of averaged epochs.
6.8. Grand a6erage
If the mean or median evoked response of a larger
number of subjects (e.g. N = 20) is of interest, the
software supplies the possibility of automated averag-
ing across a specified group of pre-evaluated and
saved individual datasets. In the grand average menu,
the user can load a text file (profile) containing the
directory paths of the corresponding data sets. All
features available for single subject analysis like filter-
ing, averaging mode selection, data display and statis-
tics are applicable by the grand average for
inter-individual evaluation.
7. Statistics
The statistical menu is subdivided into four parts:
process, descriptive, t -test and Wilcoxon test.
7.1. Process
Activating the process item, displays the number of
rejected and accepted epochs. Further more, the per-
centile fraction of the raw data contributing to the
averaged epochs is given as well as the size of the
input data file and the averaged data.
7.2. Descripti6e
For each channel the mean, standard deviation,
minimum and maximum amplitudes of the averaged
epochs and the input data can be displayed.
The statistical significance of the numerical signal
differences between two channels, particularly with re-
spect to differences between two arteries due to
evoked perfusion, can be evaluated by the parametric
t -test for dependent samples and its nonparametric
alternative, the Wilcoxon test (Spence et al., 1990). In
both cases, the tested null hypothesis is that the aver-
aged signal values 61(ti ) and 62(ti ) of two channels
have the same mean (H0: 61(ti )-62(ti ) = 0), where ti
represents the i -th sampled latency of the epoch inter-
val. If the averaged velocity curve is described by M
data points the tests are repeated for all sampled time
points ti of the epoch (i = 1, 2,…, M ). In these tests
the assumption needs to be made that the velocity
values of different epochs were statistically indepen-
dent for the latencies ti.
 M. Deppe et al. / Journal of Neuroscience Methods 75 (1997) 147–154
7.3. t -Test
The t -test parameter T will be calculated at all time
points ti and can be displayed as a function T (ti ). T (ti )
values beyond the critical value TpN for the error prob-
ability p and N ⌧ 1 degrees of freedom indicate signifi-
cant differences, where N represents the number of
averaged epochs.
7.4. Wilcoxon -Test
The results of the Wilcoxon test will also be given as
a function W (ti ), where W is equal to ‘1’ if 61(ti ) is
significantly larger than 62(ti ) and ‘ ⌧1’ if 61(ti ) is
significantly less than 62(ti ). W is ‘0’ if no significant
difference occurs at the freely selectable error level p
(Fig. 1, right column).
8. Data export
AVERAGE 1.30 supports three problem-specific
ASCII text output formats. These are DADISP® (DSP
Development Corporation, 1991a,b; 1992), SAS® (SAS
Institute Inc., 1989) and personal computer text files.
DADISP® is the standard saving format which also
can be read by AVERAGE. Raw data files, extracted
epochs, mean and median epochs, standard deviations
and upper and lower quartile points can be exported
into this format. Information about the acquired data
such as sample rate, the name of the dataset, the
channel’s name(s), time and comments are provided as
text in the dataset header (DSP Development Corpora-
tion, 1991b).
8.1. SAS
The data import into the statistic software system
SAS® is supported by the possibility to automatically
create a SAS®-Job which includes all necessary infor-
mation (statements and data) to generate a SAS® data-
set. The statement file can be expanded by the user with
further analysis statements (e.g. ANOVA) or with com-
mands for graphical output.
8.2. Text files
If the data is exported as a plain text file, no header
is saved. The data channels appear only as text columns
plus an additional channel representing the latency in
seconds for the corresponding data points. The advan-
tage of this structure is that the data is compatible with
most data import functions of commercially available
software.
153
9. Conclusion
AVERAGE for Windows® was designed as an easy
to use off-line data averaging and analyzing tool for
evoked cerebral blood flow measured by transcranial
Doppler ultrasonography. AVERAGE is of particular
value if arterial blood flow velocities are modified by
sophisticated paradigms and monitored by TCD, called
functional TCD (fTCD). In contrast to other computer
software for processing and averaging of electrophysio-
logical (e.g. Billings, 1981; Simmons, 1985; Stromquist
et al., 1990; Alarcon et al., 1991; Hedwig and Knepper,
1992) or laser Doppler data (Scheffler and Rieger,
1990), the present software is tailored to the signal
characteristics of transcranial Doppler spectrum envel-
ope curves and provides statistical methods for the
analysis of event related, uni- and bilateral perfusion
changes of the basal cerebral arteries. Due to the ver-
satile export functions the software is not only a self
consistent analysis tool, but can be regarded as an
interface between the raw data provided by TCD
devices and further self-tailored data processing tools,
and commercially available software as well. Distribu-
tion information about the most actual version is
available via Internet (URL: http://neurologie.uni-
muenster.de/AVERAGE/)
Acknowledgements
The authors gratefully thank Marcus Bäcker, cand.
med., Beate Diehl, MD, Thorsten Huber, cand. med.,
Rainer Merz, Dipl.-Ing. and Thomas Schimke, cand.
med. for their inspiring ideas and constructive criticism
during the evaluation phase.
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